The long-term objective of this proposal is to obtain safe and effective vaccines for the prevention of the most common respiratory viruses of childhood, namely respiratory syncytial virus and human parainfluenza viruses, type 1 and 3. In spite of their epidemiologic importance, no vaccines exist for these pathogens. In this program it is proposed that the murine type 1 parainfluenza virus, Sendai virus, is an effective vaccine for its human cognate (human parainfluenza virus type 1; hPIV1). Based on our previous demonstration of SV-induced protection against hPIV1 in non-human primates and preliminary success in manipulating the cDNA of SV obtained through reverse genetics, we propose that SV can serve as an effective vaccine for hPIV1 and as a vaccine backbone for additional paramyxoviral antigens. The Paramyxovirus Vaccine Program at SJCRH integrates pre-clinical and clinical research and involves members of the Departments of Infectious Diseases, the Division of Virology and the Department of Immunology. This integrated, multidisciplinary approach is essential to ultimately determine the immunologic and virologic features that reliably predict paramyxovirus vaccine efficacy. The Program consists of 3 Projects: Project 1 - Recombinant Sendai virus as a novel paramyxovirus vaccine (PORTNER); Project 2 - Immune response and vaccine efficacy in a rodent model (HURWITZ); and Project 3 - Clinical and primate paramyxovirus vaccine evaluation (SLOBOD). The strengths of the Program are based in the strength of Sendai virus as a vaccine backbone and in the experience, skills and diversity of the assembled investigators working together towards a unified objective. Ultimately, this program will yield (1) a candidate respiratory virus vaccine; (2) reagents including a panel of 12 recombinant Sendai virus vaccines (differing according to target gene identity and mode of expression), monoclonal antibodies, purified recombinant proteins of hPIV-3 and RSV; and (3) information which can be applied to the study of paramyxovirus vaccine development, including T and B cell studies of durable immunity to these most common respiratory viruses. Taken together, this comprehensive program has a high likelihood of success, measured as the identification of protective and safe respiratory virus vaccines.